Haemophilia A is an inherited bleeding disorder caused by deficiency or dysfunction of coagulation factor VIII (FVIII) activity. The clinical manifestation is not on primary haemostasis—formation of the blood clot occurs normally—but the clot is unstable due to a lack of secondary thrombin formation.
Haemophilia A is currently treated by intravenously injection of coagulation factor FVIII which is either isolated from blood or produced recombinantly. Treatment can be either on-demand or prophylactic. Recent published data support that prophylaxis has significant advantages over on-demand treatment. These include reduction in bleeding frequency and lower risk of developing haemophilic arthropathy, both resulting in a better quality of life for the patients. However, while prophylaxis enables a virtually symptom-free life for the patients, it requires frequent injections in a peripheral vein, typically three times a week, which is known to be painful, difficult, and time consuming. In addition, repeated venipuncture is not always possible in young children. Consequently, a product supporting less frequent administration and/or administration would to a greater extent enable regular prophylactic treatment.
It has long been known that coupling of polymers like for example polyethyleneglycol (PEGs) or polysialic acids (PSAs) to a protein leads to increased circulation time, increased resistance towards proteases and reduced immunogenicity. There is, however, still a need in the art for FVIII variants having a prolonged circulatory half life.